Adenosine, an endogenous purine nucleoside, is ubiquitous in mammalian cell types. Adenosine present in the plasma and other extracellular fluids mediates many of its physiological effects via cell surface receptors and is an important regulatory species. Adenosine has the formula:

Adenosine receptors are generally divided into three major subclasses, A1, A2 and A3, on the basis of the differential affinities of a number of adenosine receptor agonists and antagonists for the receptors, their primary structures and the secondary messenger systems to which they couple.
Various adenosine A3 receptor agonists and uses therefor are taught in the prior art.
WO 95/02604 (the contents of which are incorporated herein by reference) discloses A3 adenosine receptor agonists and their use as locomotor depressants, hypotensive agents, anxiolytic agents, cerebroprotectants and antiseizure agents.
U.S. Pat. No. 5,573,772 and related U.S. Pat. No. 5,443,836 claim the use of adenosine A3 agonists for applications where ischaemic preconditioning is beneficial, for example cardioprotection.
WO 98/50047 and WO 99/20284 also relate to ischaemic protection. WO 98/50047 claims methods of administering a compound having A3 agonist activity and a compound (whether the same compound or a different one) having A1 agonist activity or A2 antagonist activity. WO 99/20284 claims a method for preventing or reducing ischaemic heart damage by administration of at least two cardioprotectants, of which one may be an A3 agonist.
WO 01/19360 claims the use of A3 receptor agonists to achieve the following effect:                induce G-CSF secretion        induce proliferation or differentiation of bone marrow or white blood cells        prevent or treat leukopenia        prevent or treat toxic side effects of a drug (e.g. drug-induce leukopenia or weight loss)        inhibiting abnormal cell growth        treating cancer.        
WO 01/083152 relates to the use of adenosine A3 receptor agonists to activate natural killer (NK) cells whilst WO 02/055085 teaches their use to inhibit viral replication.
WO 02/066020 proposes the use of adenosine A3 receptor agonists to modulate the activity of glycogen synthase kinase 3β.
Adenosine receptor ligands are described in the following documents:                U.S. Pat. No. 6,048,865 (A1 ligands)        WO 01/60835 (A2 antagonists)        WO 00/23447 (A1 and A2 ligands)        WO 92/05177 (A1/A2 agonists)        WO 92/05177 (A1/A2 agonists)        WO 95/28160 (A1/A2 agonists)        EP 277917 (A2 ligands)        WO 86/00310 (A2 ligands)        EP 1241176 (A3 agonists)        WO 01/23399 (A3 agonists)        WO 02/055521 (A2a antagonists)        WO 93/23418 (A1/A2 antagonists)        WO 95/07921 (A1 agonists)        WO 98/16539 (A1 ligands)        WO 02/055085 (A3 agonists)        WO 96/12496 (A1 agonist).        
The article “Adenosine Receptor Ligands-Recent Developments Part I. Agonists”, C. E. Muller, Current Medicinal Chemistry 2000, 7, 1269-1288 reports on the developments in the field of adenosine receptor agonists, including A3 receptor agonists.
The above publications are all included herein by reference. The art therefore includes adenosine receptor agonists which are adenosine analogues characterised by specific variations which make the compounds capable of binding to and acting on one or more adenosine receptors. More particularly, the skilled person knows that there exists a class of adenosine analogue-type A3 receptor agonists.
Adenosine analogue-type A3 receptor agonists are familiar to the skilled reader and will require no further explanation to the skilled reader. Nonetheless, it may be of assistance to describe that adenosine analogue-type A3 receptor agonists may have an N6 nitrogen which may be identified with the N6 nitrogen of adenosine and is usually substituted by at least one substituent. Such agonists include without limitation compounds of the formula:
wherein    D is N or CH;    E is O, S or CH2;    X1 is an N6 substituent;    X2 (the 4′ substituent) is hydroxymethyl, (C1-C3)alkoxymethyl, (C3-C5)cycloalkoxy methyl, carboxy, (C1-C3)alkoxycarbonyl, (C3-C5)cycloalkoxycarbonyl, 1,1-aminoiminomethyl, 1,1-(mono-N- or di-N,N—(C1-C4)alkylamino)iminomethyl, 1, 1-(mono-N—or di-N,N—(C3-C5)cycloalkylamino)iminomethyl, carbamoyl, mono-N— or di-N,N—(C1-C4)alkylaminocarbonyl, mono-N— or di-N,N-(C3-C5)cycloalkylaminocarbonyl or N—(C1-C4)alkyl-N—(C3-C5)cycloalkylaminocarbonyl;    X3 and X4 are each independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, ORa NRaRb, where Ra and Rb are independently hydrogen (most preferably X3 and X4 are OH), alkyl, aralkyl, carbamoyl, alkyl carbamoyl, dialkylcarbamoyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, aryloxycarbonyl, or, when X3 and X4 are both ORa, the two Ra groups together may form
where Rc is hydrogen or alkyl,
where Rd and Re are independently hydrogen, alkyl, or together with the carbon atom to which they are attached may form a 1,1-cycloalkyl group;    X5 is H, halogen, (C1-C10)alkyl, fluorinated (C1-C10) alkyl (e.g. trifluoromethyl), (C1-C10) alkoxyalkyl, (C1-C10)alkoxy, (C1-C10)alkylether, (C1-C10)thioalkoxy, (C1-C10)alkylthio, amino, (C1-C10)alkylamino, —COX6R25 where X6 is O or NH and R25 is (C1-C4)alkyl optionally terminally substituted by an aryl or a heteroaryl group [for example phenyl or a 5- or 6-membered heteroaryl group] and additionally or alternatively terminally substituted by hydroxy, (C2-C10)alkenyl, (C2-C10)alkynyl, or is (C2-C10)alkenyl or (C2-C10)alkynyl in either case terminally substituted by an aryl or heteroaryl group [for example phenyl or a 5- or 6-membered heteroaryl group] and, when having a terminal methylic carbon atom, optionally further terminally substituted by hydroxy. Alkyl groups comprised in X5 substituents are preferably linear.
Preferred values for the above-defined symbols are as follows:    D is N;    E is O;    X2 is mono-N— or di-N,N((C1-C4) alkylaminocarbonyl, mono-N— or di-, N—(C3-C5) cycloalkylaminocarbonyl or N—(C1-C4) alkyl-N—(C3-C5) cycloalkylaminocarbonyl and especially mono-N—(C1-C4) alkylaminocarbonyl;    X3 is OH or NH2;    X4 is OH;    X5 is H, halogen, ((C1-C10) alkyl and especially (C1-C4) alkyl, trifluoromethyl, (C2-C10) alkenyl, (C2-C10) alkynyl, or either of the latter two groups where terminally substituted as described above, X5 more preferably being H, chloro, bromo, iodo, (C1-C4) alkyl and especially methyl, or trifluoromethyl.
It will be appreciated that any one or more of D, E, X2, X3, X4 and X5 may be one of the preferred species listed above; most desirably all are preferred.